title: Exome sequencing as a diagnostic tool for pediatric-onset ataxia.
abstract: Ataxia demonstrates substantial phenotypic and genetic heterogeneity. We set out to determine the diagnostic yield of exome sequencing in pediatric patients with ataxia without a molecular diagnosis after standard-of-care assessment in Canada. FORGE (Finding Of Rare disease GEnes) Canada is a nation-wide project focused on identifying novel disease genes for rare pediatric diseases using whole-exome sequencing. We retrospectively selected all FORGE Canada projects that included cerebellar ataxia as a feature. We identified 28 such families and a molecular diagnosis was made in 13; a success rate of 46%. In 11 families, we identified mutations in genes associated with known neurological syndromes and in two we identified novel disease genes. Exome analysis of sib pairs and/or patients born to consanguineous parents was more likely to be successful (9/13) than simplex cases (4/15). Our data suggest that exome sequencing is an effective first line test for pediatric patients with ataxia where a specific single gene is not immediately suspected to be causative.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Sawyer
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.forename: Chandree L
authors.initials: CL
authors.lastname: Beaulieu
authors.forename: David
authors.initials: D
authors.lastname: Dyment
authors.forename: Amanda
authors.initials: A
authors.lastname: Smith
authors.forename: Jodi
authors.initials: J
authors.lastname: Warman Chardon
authors.forename: Grace
authors.initials: G
authors.lastname: Yoon
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: Oksana
authors.initials: O
authors.lastname: Suchowersky
authors.forename: Victoria
authors.initials: V
authors.lastname: Siu
authors.forename: Lisa
authors.initials: L
authors.lastname: Murphy
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Bulman
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Mark
authors.initials: M
authors.lastname: Tarnopolsky
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
mesh_terms: D002170:Canada; D002524:Cerebellar Ataxia / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D059472:Exome; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D025202:Molecular Diagnostic Techniques; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA